This application is based on, and claims priority of, Canadian Patent Application No. 2,358,575 filed on Sep. 26, 2001.
Not Applicable.
The present invention relates to the field of dissolution measurement and, more particularly, to a low-speed precision stirring/mixing device for repeatable dissolution of solid or granular material.
A solid oral pharmaceutical product, such as a tablet or capsule, is generally composed of a mixture of active ingredient(s) and excipient (i.e., pharmacologically inactive ingredients compressed into a desired shape). When the product is administered to a patient, it is expected that the active ingredient will be released into the gastrointestinal (GI) tract in a predictable and reproducible manner which, in turn, is absorbed into systemic circulation to elicit the desired effect. There are a number of factors such as: nature and composition of active and inactive ingredients, manufacturing process, and/or storage conditions which can alter the drug release characteristics of a product, and consequently the outcome in a patient.
Generally used methodology to assess the drug release characteristics of products in humans is known as a bio-availability and/or bio-equivalence study, also commonly termed as a bio-study. In these studies, following a set protocol, a drug product is administered to human volunteers and a number of blood samples are withdrawn at different time intervals. Using sophisticated analytical techniques such as chromatography, these blood samples are then analyzed to determine the drug levels. The resulting blood concentration-time profiles form the basis of bio-availability and bio-equivalence assessment. Based on the area under the profile and its peak value (highest observed concentration, usually denoted by Cmax), the extent and rate of drug release and absorption is established and compared to profiles obtained from different products. This is the fundamental concept in the drug release evaluation to establish safety, efficacy and quality aspects of a drug product. Any time that (a) a new product is developed, or (b) significant changes are made to an existing product, or (c) the manufacturing process is altered, the quality of the products, with respect to their drug release characteristics, has to be tested following this route.
Ethical concerns severely limit the conduct of these studies in humans. Further, conducting these bio-studies is usually very expensive and time consuming. Thus, because of cost, time and ethical considerations, it is not always possible to conduct drug release studies in humans. As a result an in vitro drug release evaluation test is a commonly used alternative. For this purpose, an in vitro test (known as a dissolution test) has been developed and has become a tool for both product development and quality assurance. This test is routinely conducted at every stage of drug product development, manufacturing, and post-manufacturing assessments.
In a drug dissolution test, drug release from a product is determined in an aqueous dissolution medium (water or buffers) with mild agitation or stirring to simulate drug release in GI environments. The logic behind assessing the drug release in water or aqueous buffer solution is that, if a drug is to be absorbed from the GI tract into the systemic circulation, the drug has to be in a solution form. Thus, any changes in drug release characteristics in solution should, at least in theory, be reflected in corresponding changes in drug availability in systemic circulation.
Presently, drug dissolution testing is conducted using recommended compendial methods, such as the U.S. Pharmacopoeia. Four different types of apparatus, based on different mixing methods are available commercially and have compendial recognition. These apparatuses are known as: paddle; basket; flow-through; and reciprocating cylinder.
Of these four types of apparatus, the paddle apparatus is the most commonly used. As may be seen in FIG. 1, the paddle apparatus provides a mixing vessel 2 (which is typically round-bottomed) into which an aqueous medium 4 is placed. Stirring of the aqueous medium 4 is achieved by means of a T-shaped paddle 6 which is supported within the vessel and rotated by a motor-driven spindle (not shown). A typical paddle apparatus normally has six or twelve dissolution vessels 2, to enable simultaneous testing of multiple samples.
When a product (tablet or capsule) is dropped into the dissolution vessel 2, the stirring/mixing is achieved by rotating the paddle 6 at a desired speed, typically 50-100 rpm. At specific times, samples of the dissolution medium are withdrawn and the percentage of the drug dissolved is determined using any of the conventional analytical methods such as UV or liquid chromatography. Cumulative drug release as a percentage of the dosage strength is then calculated and reported, describing the drug release characteristic in vitro.
A limitation of the conventional paddle apparatus is that the rotating paddle 6 creates a vortex effect, allowing the disintegrated (powdered) product 8 to accumulate at the bottom of the vessel 2. This reduces the available surface area of solid particles, reducing interaction between these particles and the dissolution medium, which leads to artificially low dissolution rates. This can cause the current methodology to provide inaccurate and non-repeatable estimates of drug release rates.
Low speed mixing devices are known in non-analogous arts, such as dough making. Examples of such devices are shown in Canadian Patents No. 1,052,766 to Kramer and No. 1,038,858 to Smader, in which a kneading arm has a shape that conforms approximately to the bottom shape of the mixing vessel. However, this arm is the only active part in the mixing of the material, and is designed for high torque mixing to provide a high shearing effect to force the material together. Lumps and irregularities in cohesive material are broken by high shearing forces within the dough. This can be efficient with highly cohesive material (such as flour and water), but will leave material at the bottom of the mixing vessel in any other situation.
U.S. Pat. No. 4,197,018 to Groen discloses a mixer for a cooking vessel in which an arm follows closely the shape of the bottom part of the vessel. The principal effect of this arm is to scrape the bottom of the vessel. A stirring blade pushes the material around. This is only useful in a context of floating material and to prevent any material from sticking to the vessel. The combined surface of the arm and of the stirring blade is far too large for an efficient mixing of material, and is designed more to push the material around the vessel so that it will not stick to the vessel.
The use of brushes for mixing material is disclosed in several United States patent documents (see, for example, U.S. Pat. Nos. 4,630,932, 1,417,965) and Japanese patent documents (see, for example, JP-09-150046, JP-07-232047, JP-07-108152, JP-57-053229, JP-57-004218, and 55-099328). However, the devices disclosed in these patents are designed for high-speed mixing/grinding (thus high-shear) to provide disturbed fluid flow effects to mix/break the material.
U.S. Pat. No. 5,908,241 discloses a variation on the preceding devices, in which brushes are replaced by a helical open coil for mixing. This device also relies on the high shear fluid flow effects to mix/break the material.
These prior art mixing devices are not suitable for high precision mixing, such as is required in dissolution testing. Therefore, an apparatus and method for improved precision mixing remains highly desirable.
Accordingly, the present invention provides a low-speed precision stirring/mixing device for dissolution of solid or granular material for use in measuring the release characteristics of an active ingredient in a pharmaceutical product.
Thus, an aspect of the present invention provides a mixing device for low speed precision mixing of contents of a vessel. The mixing device comprises a support member adapted to be rotatably supported in spaced relationship from a bottom portion of the vessel and separated therefrom by a gap; and a brush assembly depending from the support member for sliding engagement with the bottom portion of the vessel. Low speed rotation of the support member within the vessel causes the brush assembly to sweep the bottom portion of the vessel while mixing the contents of the vessel.
Preferably, the brush assembly comprises a resilient coil or a plurality of filamentary or lamellar elements, affixed to the support member.